N-{4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-N′-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide (international non-proprietary name (INN): cabozantinib) represented by chemical structure
is a RET, MET, KIT and VEGFR2 receptor tyrosine kinase inhibitor. It is currently marked for the treatment of thyroid cancer under the brand name Cometriq. Cometriq capsules contain cabozantinib as its (L)-malate salt. Cabozantinib is classified as a BCS class II compound having a low solubility and high permeability. The malate salt shows an enhanced solubility when compared with cabozantinib free base.
The above mentioned compound will be referred to in the present application by its international non-proprietary names, i.e. cabozantinib. A salt of cabozantinib will be referred to as cabozantinib salt e.g. cabozantinib succinate or cabozantinib succinic acid salt.
International patent application WO2005/030140 discloses cabozantinib. Further the application discloses processes for the preparation of cabozantinib, pharmaceutical preparation of cabozantinib and therapeutic application thereof.
Patent application CN 104109124 discloses a cabozantinib 0.5 malate crystal, pharmaceutical compositions and therapeutic applications thereof for the treatment of tumor associated diseases. The crystal is characterized by a power X-ray diffraction pattern comprising the diffraction peaks at 2theta angles: 5.48, 10.88, 15.24, 21.97, 24.56 when measured using Cu-Kalpha radiation.
International patent application WO2010/083414 discloses the (L)-, (D)- and (D,L)-malate salts as compounds (I), (II) and (III). WO2010/083414 further discloses the polymorphic Forms N-1 and N-2 of compounds (I) (II) and (III). The (L)-malate salt is reported to be non-hygroscopic and having chemical stability.
Example 1 of WO2010/083414 provides a concrete process for the preparation of cabozantinib free base. Example 2 provides a concrete process for the preparation of cabozantinib (L)-malate crystalline Form N-1 comprising a final crystallization step from acetonitrile as the solvent. The XRPD spectrum of (L)-malate crystalline Form N-1 is also disclosed. Example 4 provides a concrete process for the preparation of cabozantinib (L)-malate crystalline Form N-2 comprising a final crystallization step from a binary system of solvents wherein the solvents are tetrahydrofuran and methyl isobutyl ketone. Seeds are required for crystallization of Form N-2. The XRPD spectrum of (L)-malate crystalline Form N-2 is also disclosed. Form N-2 has been selected for commercial development.
Hence, the cabozantinib (L)-malate salt exists in two polymorphic forms that need to be controlled in the formulation of the drug. WO2010/083414 discloses in Table 1 on page 9 that there was no salt formation between cabozantinib and acetic acid or succinic acid.
In view of the above mentioned drawbacks, there is the need to provide forms of cabozantinib with physicochemical properties which render them suitable for pharmaceutical formulation; in particular solid forms with a balanced profile of appropriate physicochemical properties such as suitable solubility, chemical stability, favorable morphology, improved filterability, appropriate hygroscopicity. There is, as well, the need for pharmaceutical compositions comprising the same.